Associate Professor of Medicine
5 Maloney, Suite 504, Room 509
3400 Spruce Street
Philadelphia, PA 19104-4283
Office: 215-662-2454
Fax: 215-662-4500
Email : vonfeldt@mail.med.upenn.edu
Funding source: NIH
Program Summary
Inflammatory diseases, including arthritis, are often associated with
reduced life expectancy, due in part to an excess of cardiovascular disease
deaths. Low dose methotrexate (MTX) therapy is a mainstay for the long-term
management of arthritis. Arthritis patients with cardiovascular disease
who are treated with MTX have higher cardiovascular mortality rates than
their peers treated with alternative disease-modifying anti-rheumatoid
drugs (DMARDs). In addition, there is considerable inter-individual variation
in the clinical efficacy of MTX, and about 30% of patients experience
unacceptable toxicity. Objective methods to identify those for whom MTX
therapy will be effective and minimally toxic, without greatly enhancing
cardiovascular disease risk, would therefore contribute significantly
to the clinical management of arthritis and other inflammatory conditions.
MTX inhibits dihydrofolate reductase, an enzyme involved in purine synthesis and a component of the broader folate/Hcy metabolic axis. Methylenetetrahydrofolate reductase (MTHFR) is pivotal in controlling the distribution of folate derivatives between the two main constituent pathways that serve cellular methylation reactions and nucleic acid synthesis. In addition, methionine synthase (MTR), cytathionine ß-synthase (CBS), and methionine synthase reductase (MTRR) are involved in reactions that control Hcy concentrations. Functional polymorphisms of MTHFR, MTR, CBS and MTRR significantly modify intracellular levels of folate derivatives and/or circulating Hcy levels, thereby increasing the risk of Hcy-associated pathologies. These polymorphisms, alone or in combination, may “prime” the folate/Hcy metabolic axis to respond to MTX by adopting an extreme pathogenic phenotype, and may also be significant determinants of the efficacy and toxicity associated with the drug.
In this study, we will assess the above in a pharmacogenetic analysis of 300 arthritis patients who are about to embark on MTX therapy. Pre-treatment and in-treatment folate derivative, B vitamin and Hcy concentrations will be determined together with MTHFR, MTR, CBS, and MTRR genotypes to establish whether there are particular phenotypic and/or genotypic variables that can be used to predict MTX efficacy and toxicity, and the likelihood of MTX-mediated enhancement of Hcy-associated disease risk.
This research may establish the genetic parameters that mandate the treatment of arthritic patients with either MTX or an alternative DMARD. It has the potential to facilitate individualized treatment protocols that are less empirical and therefore more effective, and to reduce the incidence of cardiovascular co-morbidity.
Associated Faculty
Alexander S. Whitehead, Ph.D., Dept of Pharmacology
Patient Summary
Methotrexate is a commonly used drug to treat patients with Rheumatoid
Arthritis, Lupus and Psoriatic Arthritis. In this study we are trying
to determine whether certain genes predispose you to developing toxic
side effects while you are taking the drug. methotrexate. We know that
certain drugs can adversely affect some metabolic pathways. We are looking
at some genes (for example the MTHFR gene) that may produce too many toxic
byproducts (such as homocysteine) when you take methotrexate. By studying
patients who are on methotrexate, we may be able to predict, which genes
can predispose to toxic side effects of methotrexate, and develop a gene
panel to help rheumatologists choose the right medications for treatment
of arthritis.
Entry Criteria for the study
You have an arthritic condition that requires treatment with methotrexate
Some exclusion criteria may apply
Study
You volunteer, with informed consent to give 3 tubes of blood for this
test that evaluates certain genes that can predispose you to toxicity
from methotrexate.
Compensation:
You are reimbursed for travel expenses
Contact Person:
Janice Prodell-Glisson , RN
215-615-3045
janice@spirit.gcrc.upenn.edu
Funding Source: Immunex
Program Summary
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting
primarily the joints and often extra-articular sites. RA has significant
inpact on work disability; morbidity and mortality of afflicted patients.
In addition, a significant rate of untoward events is often associated
both with RA and with the medications used to treat RA.
Treatment for RA is standardized but influenced by many factors including physicians and patient preferences, severity of symptoms and know tolerability and effectiveness of medications. Treatments are often changed in RA patients for a variety or reasons that include a lack or loss of effectiveness as well as untoward events.
The types and patterns of treatments used in clinical practice by rheumatologists to treat RA have not been will documented and the rate and reasons for changing medications are not well understood. Additionally, while several studies suggest that the rate of certain serious adverse events is higher in-patients with RA than the general population, their actual rate in clinical practice is unknown.
RADIUS 1 is designed to systematically collect and document use patterns, effectiveness and safety of DMARD treatments currently used in the management of rheumatoid arthritis (RA). It is anticipated that study data may help improve the quality of information upon which clinical decisions are based. Patients eligible for inclusion in the study will be male and female adult patients who fulfill the 1987 American Rheumatism Association criteria for the classification of RA and who currently require a new DMARD (change or addition) including azathioprine, cyclosporine, etanercept, gold hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, or sulfasalazine. This is a prospective, multicenter, observational study. After an initial baseline evaluation, the patient will continue to be seen at intervals deemed appropriate by his/her physician. Clinical data relevant to the routine care and management of the patient will be collected for a least 2 years. This is a prospective, multicenter, observational study.
Associated Faculty
H. Ralph Schumacher, M.D., Division of Rheumatology
Sharon Kolasinski, M.D., Division of Rheumatology
Patient Summary
Rheumatoid Arthritis is a chronic illness, affecting most of the joints
in your body. The inflammation associated with this disease can cause
damage to the joints, thereby creating deformities, and ultimately disability.
Although there are many medicines currently available that can control
the disease, there is no cure. RADIUS 1 is designed to systematically
collect and document use patterns, effectiveness and safety of DMARD treatments
currently used in the management of rheumatoid arthritis (RA). It is anticipated
that study data may help improve the quality of information upon which
clinical decisions are based. Patients eligible for inclusion in the study
will be male and female adult patients who fulfill the 1987 American Rheumatism
Association criteria for the classification of RA and who currently require
a new DMARD (change or addition) including azathioprine, cyclosporine,
etanercept, gold hydroxychloroquine, infliximab, leflunomide, methotrexate,
minocycline, or sulfasalazine. This is a prospective, multicenter, observational
study. After an initial baseline evaluation, the patient will continue
to be seen at intervals deemed appropriate by his/her physician. Clinical
data relevant to the routine care and management of the patient will be
collected for a least 2 years.
Entry Criteria for the study
You are 18 years of age or older, have Rheumatoid Arthritis, and will
have a modification of your current medicine regimen.
Some exclusion criteria my apply.
Study
You volunteer, with informed consent to have an evaluation of your rheumatoid
arthritis. This includes an interview, questionnaires and an examination.
Compensation:
You are reimbursed for your travel expenses.
Contact Person:
Janice Prodell Glisson, RN 215-615-3045, janice@spirit.gcrc.upenn.edu
Funding source: Lupus Foundation | American Heart Association | Lupus Research Institute
Program summary
Cardiovascular and cerebrovascular events are the third leading cause
of death in Systemic Lupus Erythematosus(SLE) patients. SLE is much more
common in women than in men, and can affect people at any age, but usually
between the ages of 20-50. Heart disease in this age group is very unusual,
therefore the high morbidity and mortality of cardiovascular disease in
SLE patients is extraordinary. Because of their disease or treatment,
many of these SLE patients have risk factors for coronary artery disease,
including hypertension and elevated cholesterol. However, stratification
of their disease by risk factors alone does not reliably predict cardiac
(or cerebrovascular) events. Since these patients are not the usual group
of patients that have cardiovascular disease, simple diagnostic modalities
to screen for cardiac disease in this group of patients has not been well
studied.
The advent of coronary electron beam computed tomography (EBCT) that detects atherosclerotic coronary artery disease by measuring calcium deposition in the walls of coronary arteries may provide rheumatologists with a screen for SLE patients with risk factors to identify those at risk of premature atherosclerosis. Although EBCT is now a well established tool in more conventional populations at risk for coronary artery disease, it has not been used to evaluate any group of SLE patients. It would be a breakthrough in evaluation and management of SLE patients with known risk factors for cardiovascular disease, if we could identify certain subsets of SLE patients with coronary calcification by EBCT. Identification of these SLE patients at risk would prompt aggressive management of these patients, and (hopefully) decrease their risk for fatal and nonfatal cardiac events.
Associated Faculty
Dan Rader, M.D., Division of Cardiology
Lisa Scalzi, M.D., Division of Rheumatology
Patient Summary
Patients with systemic lupus erythematosus (lupus for short) have an increased
risk of heart attacks and strokes. Most patients with lupus are young
women in childbearing years, and heart attacks and strokes do not usually
occur in this young population. Therefore, it is important to try to identify
these SLE patients who are at risk of heart attacks and strokes
Heart Disease is common in patients with Lupus. Currently, your doctor can not predict whether you will develop atherosclerotic heart disease. Electron beam computed tomography (EBCT) is a new type of xray study that detects atherosclerotic heart disease by measuring calcium deposition in the walls of coronary arteries.
With this new technology, we can detect atheroslcerosis in the arteries of the heart. We are studying patients with this new technology. We are also studying other laboratory markers that can be associated with premature atherosclerosis. We are evaluating patients with lupus by EBCT to determine if this new xray method can detect atherosclerotic heart disease in patients with Lupus who are at risk of heart attacks. It may provide information that may help your doctor predict whether you are at risk of heart disease. With this information, your doctor may change the treatments he/she uses to treat you.
Entry Criteria for the study
You have Lupus
Some exclusion criteria my apply
Study
You volunteer, with informed consent to have an evluation for risk factors
for heart disease, which includes a questionnaire, some blood tests and
an EBCT scan
Compensation:
You are reimbursed for travel expenses
Contact Person:
Eleni Nackos, 215-615-3047
nackose@uphs.upenn.edu
Funding source: American Heart Association
As Systemic Lupus Erythematosus (SLE) patients are surviving the life threatening complications of lupus disease activity, they are facing the significant morbidity and mortality of premature cardiovascular events. Hyperhomocysteinemia has been found to occur more frequently in SLE than age matched controls and has been identified as an independent risk factor for atherothrombotic events in SLE. This study looks at the prevalence of hyperhomocysteinemia, and the contribution of genetic polymorphisms affecting folate/homocyteine metabolism to the risk of premature ASCVD in SLE. We will also correlate other risk factors implicated in ASCVD including coronary calcification by EBCT, and other risk factors for premature atherosclerotic heart disease such as hypertension, hyper-cholesterolemia, and obesity and risk factors postulated to be of particular significance in SLE, including; antiphospholipid antibodies, antibodies to Lp(a) and antibodies to oxidized LDL.
Associated Faculty
Dan Rader, M.D., Division of Cardiology
Alexander S. Whitehead, Ph.D., Dept of Pharmacology
Patient summary
Patients with systemic lupus erythematosus (lupus for short) have an increased
risk of heart attacks and strokes. Most patients with lupus are young
women in childbearing years, and heart attacks and strokes do not usually
occur in this young population. Therefore, it is important to try to identify
these SLE patients who are at risk of heart attacks and strokes.
With a new technology called electron beam computed tomography, (EBCT for short), we can detect atheroslcerosis in the arteries of the heart. We are studying patients with this new technology. We are also studying other laboratory markers that can be associated with premature atherosclerosis.
Other patient populations who have heart attacks and stroke shave high levels of homocysteine in their blood. In this study we are also asking the question: Do patients with lupus have certain genes that predispose them to have high homocysteine levels.
The results of this study could result in a diagnostic test to evaluate patients with lupus. If lupus patients had a specific gene that predisposed them to high homocysteine levels, certain medications could be avoided, and certain treatments could be given.
Entry Criteria for the study
You have Lupus
Some exclusion criteria my apply
Study
You volunteer, with informed consent to have an evaluation for risk factors
for heart disease, which includes a questionnaire, some blood tests and
an EBCT scan. In addition you give consent to do a blood test that evaluates
certain genes that can predispose you to high homocysteine levels.
Compensation:
You are reimbursed for travel expenses
Contact Person:
Janice Prodell Glisson, RN 215-615-3045, janice@spirit.gcrc.upenn.edu
Program Summary
This proposed study will attempt to ascertain what proportion of the patients
treated for fragile fractures of the wrist or hip in the Emergency Department
of the Hospital of the University of Pennsylvania receive osteoporosis
follow-up. It would also estimate the proportion of patients who started
treatment for osteoporosis after a fragile wrist or hip fracture.
The participants in this retrospective observational study will be selected from a medical records review of Emergency Department visits between 1997 and 2001. Potential participants will be men or women over the age of 40 who visited the Emergency Department with a low-energy fracture of the wrist or hip typical of osteoporotic fractures.
The participants will be consented by telephone for a brief interview. The interview questionnaire will collect information on demographics, comorbidities, history of fracture, osteoporosis follow-up and current or past treatment for osteoporosis. The study design, consent form and questionnaire have already received approval from the Department of Rheumatology and the Institutional Review Board of the University of Pennsylvania.
This study has potential benefit to both the participants and to society in general. Some of the participants who did not receive osteoporosis follow-up after their fracture may decide to discuss osteoporosis with their doctor, perhaps resulting in implementation of effective therapy. Data from this study may also help to improve the approach to patients who sustain fractures at a typical osteoporotic site, both at this hospital and more generally.
Associated Faculty
Stephanie Abhul, M.D., Department of Emergency Medicine
Kate Hanna Blumner, medical student, University of Pennsylvania
Patient Summary
Osteoporosis is a condition of thin bones. Bones are strong because of
the architecture of the tissue that looks like a lattice of interconnecting
‘I beams’. The word Osteoporosis literally means porous bones.
In osteoporosis, the bone loses calcium and phosphorus, the minerals that
makes it strong, and the lattice of supporting ‘beams’ is less
dense, and the ‘beams’ are thinner. With fewer supporting ‘beams’
you have fragile bones. And that means the bones more easily fracture.
It is often called the silent disease because fractures can occur without
warning, when you least expect them.
Entry Criteria for the study
You have had a fracture and have gone to the Emergency Room at HUP
Some exclusion criteria my apply
Study
You volunteer, with informed consent over the phone to answer some questions
about osteoporosis and the treatment of your fracture
Compensation:
There is no compensation for participating in the telephone study
Contact Person:
Kate Hanna Blumner: blumner@mail.med.upenn.edu